Research Project, Project Summary Intellectual and developmental disabilities (IDDs) exact a heavy emotional and financial toll on society, affecting an estimated 1 in 6 children in the US. Developing effective therapeutic interventions to treat IDD is a challenging problem because a large number of environmental and genetic risk factors contribute to these diseases. Indeed, IDD-associated genetic variants have been identified in more than 700 genes, but each variant is present in only a small number of patients, and our understanding of how these variants contribute to the disease is limited. This high degree of genetic heterogeneity and lack of mechanistic insights confound efforts to develop effective therapies to treat IDD. If individual mutations can be grouped by shared molecular pathways, then targeting these pathways may be efficacious in large subsets of patients. The overall goal of our proposal is to develop CRANIUM, a platform that will read out the genomic, transcriptional, and neuronal phenotypic signatures of IDD genes to reveal common pathways disrupted by IDD-associated mutations.